Biodegradable matrices for drug delivery are useful because they obviate the need to remove non-degradable drug depleted devices. Many biodegradable polymers have been evaluated for their suitability for use as a matrix for drug delivery. Examples include polyesters, polycarbonates, natural and synthetic polyamides, polyphosphate esters, polyphosphazenes and polyanhydrides.
Polyanhydrides have been used as bioabsorbable materials for controlled drug delivery. Polyanhydrides degrade to dicarboxylic acid monomers when placed in aqueous medium. Several review articles have been published on polyanhydrides for controlled drug delivery applications. However, these polymers degrade in a short period, typically less than 20 weeks.
Linear polyesters of lactide and glycolide have been used for more than three decades for a variety of medical applications, including delivery of drugs. (Handbook of Biodegradable Polymers, A. Domb, J. Kost and D. Wiseman, Harwood and Brooks (1997). PLA has wide applications in medicine because of its biocompatibility and degradability into nontoxic products. Micelles and particles of the AB block copolymer poly(lactide)-b-poly(ethyleneglycol) (PLA-b-PEG) have received attention for use in intravenous injectable delivery systems for extended and targeted drug release (Gref et al., Protein Delivery-Physical Systems, L. M. Sanders and H. Hendren, Eds, Plenum Press, (1997); and Gref et al., Advanced Drug Delivery Reviews, 16: 215-233 (1995)). Similarly, U.S. Pat. No. 5,578,325 to Domb et al. describes multiblock copolymers comprising a multifunctional compound covalently linked with one or more hydrophilic polymers and one or more hydrophobic bioerodible polymers and including at least three polymer blocks. A PEG-coating on a microparticle or other polymeric device prevents the adsorption of plasma proteins and fast elimination by the reticulo endothelial system (RES).
Several liquid polymer formulations that change their viscosity have been reported including a temperartue sensitive aqueous solution of a copolymer of poly(lactic acid) [PLA] with polyethylene glycole [PEG] which is liquid at 15° C. but form a gel at temperatures above 30° C. such as when injected in the body. This system uses a solvent, water, thus forming a hydrophilic gel upon injection in tissue.
The ideal polymeric matrix for controlled drug delivery would have the characteristics of a biodegradable, solvent-free liquid or paste material that allows easy mixing in of bioactive agents to form a depot of drug at the site of injection. The desired polymeric material should be an injectable liquid or paste at room temperature while rapidly increase its viscosity shortly after injection in tissue so that it remain in the site of injection while releasing the incorporated active agents for an extended time period.
Such a polymer must be hydrophobic so that it retains its integrity and the incorporated drug for a suitable period of time when placed in biological systems, such as the body, and stable under common storage conditions, preferable room temperature, for an extended periods before use.
Fatty acids are suitable candidates for the preparation of biodegradable polymers, as they are natural body components and are hydrophobic, thus allowing retention of an encapsulated drug for longer periods of time when used for drug delivery. However, most fatty acids are monofunctional and cannot serve as monomers for polymerization. The use of functionalized fatty acids has been described in order to overcome this limitation. For example, very low molecular weight copolymers of lactic acid and ricinoleic acid prepared from crude (<88% pure) lactic acid and ricinoleic acid for use in cosmetics has been reported in U.S. Pat. No. 6,692,728 to Weipert et al.
In spite of the previously described drug delivery systems, there is still a need for a reliable polymer composition that can be injected into the body where it forms an in situ implant for the controlled release of drugs or serves as a temporary surgical implant.
It is therefore an object of the invention to provide biodegradable polyesters that are liquids or pastes at temperatures below 37° C. that allows the incorporation of active agents without the use of solvents or heat, methods of making the polyesters thereof and methods of use.